Environment International 35 (2009) 507–511

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Environment International
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / e n v i n t

Association of arsenic and kidney dysfunction in people with diabetes and validation
of its effects in rats
Jian Ping Wang a,b, Sheng Ling Wang c, Qin Lin c, Ling Zhang c, Daphne Huang a, Jack C. Ng a,b,⁎
a
The University of Queensland, National Research Centre for Environmental Toxicology, Faculty of Health Sciences, 39 Kessels Road, Coopers Plains, Brisbane, QLD 4108, Australia
b
CRC-CARE (Cooperative Research Centre for Contamination Assessment and Remediation of the Environment), SA, Australia
c
Xinjiang Centre for Disease Control and Prevention, 141 First Jianquan ST, Urumqi, Xinjiang 830002, PR China

a r t i c l e i n f o a b s t r a c t

Available online 14 September 2008 We studied villagers with and without diabetes from arsenic-endemic areas and a nearby control site in
Xinjiang Autonomous Region, PR China. Water and urinary arsenic were assayed for exposure measurement.
Keywords: Urinary NAG (N-acetyl-β-glucosaminidase), a kidney function test, blood glucose, triglyceride, cholesterol,
Arsenic
high density lipid and low density lipid were measured. Villagers from endemic areas were found to have
Diabetes
higher urinary arsenic concentrations. The NAG results also suggest that chronic arsenic exposure presents a
Kidney dysfunction
NAG, N-acetyl-β-glucosaminidase
significant adverse impact on the kidney function of villagers in the endemic areas. However, blood glucose
China levels of diabetes individuals were lower than those from the control site. These observations were validated
in rats which were chronically exposed to arsenic in drinking water. The distinct relationship between
chronic arsenic exposure and diabetes mellitus requires further investigation. A rodent model is a useful tool
for study of this type.
Crown Copyright © 2008 Published by Elsevier Ltd. All rights reserved.

1. Introduction
Adverse health effects including cancers caused by chronic arsenic
exposure are of global significance. Diabetes is another chronic health
disease that is on the increase worldwide. There have been several
epidemiological studies implicating the positive association between
arsenic exposure and diabetes mellitus.
Inorganic arsenic is classified as human (group ) carcinogen. Chronic
exposure to arsenic can cause an increased risk of cancers in the lung,
liver, kidney, bladder, and skin. Arsenic is also atherogenic and neuro-
pathogenic (IPCS, 2001; IARC, 2004). Exposure to arsenic-contaminated
drinking artesian well water in the arsenicosis-hyperendemic areas in
Taiwan has been implicated causing an endemic peripheral vascular
disease known as blackfoot disease (Lu et al., 1987). Arsenic exposure is
also related to ischemic heart disease, stroke, hypertension, and a no-
ticeable deterioration in normal renal function (ATSDR, 2004; IPCS,
2001). Arsenic poisoning has become one of the major environmental
concerns in the world as millions of people are being exposed to
excessive arsenic through consumption of contaminated drinking water
in areas such as Bangladesh, India, Taiwan, Xinjiang, Inner Mongolia and
Shanxi of China as well as certain parts of South America. The use of
arsenic-bearing coal for cooking and heating purposes in Guizhou
⁎ Corresponding author. National Research Centre for Environmental Toxicology,
Faculty of Health Sciences, The University of Queensland, 39 Kessels Road, Coopers
Plains, Brisbane, QLD 4108, Australia. Tel.: +61 7 3274 9020; fax: +61 7 3274 9003.
E-mail address: j.ng@uq.edu.au (J.C. Ng).
Province of China is also another source for chronic arsenic exposure (Ng
et al., 2003, 2005).
Although kidney cancer can be developed after chronic arsenic
exposure, and acute intoxication by arsenic can cause tubulointerstitial
nephritis following fluid imbalances. The kidney is, however, relatively
less sensitive to chronic arsenic than most other organ system (ATSDR,
2004). Chronic arsenic exposure alone can lead to nephrotoxicity in
mice (Liu et al., 2000), however in humans most studies focused on the
synergetic effect of arsenic with other elements such as cadmium
(Buchet et al., 2003; Nordberg et al., 2005; Hong et al., 2004).
Diabetes mellitus is one of the most common diseases that causes
high morbidity and mortality world wide. Chronic exposure to arsenic
has been associated with diabetes mellitus in humans (Tseng, 2004;
Lai et al., 1994; Tseng et al., 2000, 2002; Rahman and Axelson, 1995;
Rahman et al., 1996, 1998, 1999), although the evidence is not as strong
as its carcinogenicity. Previous studies of the role of arsenic in diabetes
have questioned the quality of the evidence but were supportive of the
possibility of an association (NRC, 1999, 2001; IPCS, 2001; Tseng, 2004,
Tseng et al., 2000, 2002; WHO, 2001). Although current experimental
and epidemiologic evidence are perhaps inadequate to establish
causality of arsenic exposure and diabetes (Navas-Acien et al., 2006),
the possibility of an association has drawn the attention of scientists
worldwide prompting further research.
Different species of animals including mice, rats, goats and guinea
pigs have been employed to study the effect of arsenic exposure on
glucose metabolism for decades. Arsenic compounds such as inor-
ganic AsIII, AsV and organic arsenic were used (Navas-Acien et al., 2006).
However, inconsistent results regarding the effect of arsenic exposure on

0160-4120/$ – see front matter. Crown Copyright © 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.envint.2008.07.015
508 J.P. Wang et al. / Environment International 35 (2009) 507–511

Table 1 Diabetic patients were selected based on local hospital records followed by clinical
Arsenic concentrations (µg/L) in tap water and artisan well water samples collected examinations including blood glucose, heart rate, pulse and blood pressure measurements.
from the endemic and control areas in Chepaizi, Xinjiang, PR China
2.3. Sampling — animal study
Site Water type As (µg/L)
Control area 125 district headquarter Tap water 16 Ninety six male rats (Sprague–Dawley) were divided into 4 groups and were exposed
130 district headquarter Tap water 23 to different concentrations of arsenic (0 mg/L, 5 mg/L, 15 mg/L or 30 mg/L) in their drinking
125 district 13th village Tap water 38 water for up to 8 months. Diabetic conditions were induced in 50% of the rats by a single
Endemic area 126 district headquarter Tap water 44 intravenous injection of STZ (Streptozotocin) (35 mg/kg bw) after 180–242 days. Urinary
127 district 13th village Tap water 46 arsenic and NAG (N-acetyl-β-glucosaminidase) and blood glucose were measured fort-
128 district 1st village Tap water 21 nightly and monthly, respectively.
128 district 2nd village Tap water 53 Blood glucose was analysed using a portable complete diabetes monitoring ma-
128 district 5th village Tap water 47 chine (Accu-CHEK, Australia) immediately after or prior to urine collection.
128 district 7th village Shallow ground well 36 Blood glucose tolerance test was carried out by giving rats (5 in each group) 0.2 g
128 district 8th village Tap water 20 glucose as a 20% glucose solution per 100 g body weight by gavage. Blood glucose levels
128 district 9th village Tap water 47 were measured at time intervals of 0, 15, 30, 60, 120 and 180 min.
128 district 10th village Tap water 29
128 district 12th village Artesian well 272
2.4. Water sampling
128 district 14th village Tap water 39
128 district 15th village Tap water 48
128 district headquarter Tap water 43 Eighteen water samples from local residential dwellings and centralized water
128 district construction Tap water 30 supply systems both in the endemic and control areas were collected into 3% nitric acid
129 district headquarter Tap water 22 pre-treated plastic tubes.
Water and first-void urine samples on dry ice were transferred to Australia then
stored at −80 °C until analyses.

blood glucose were reported. Developing a reliable animal model for 2.5. Total arsenic analysis
arsenic-induced diabetes is needed in order to better understand the
arsenic diabetogenic effect and its potential causal relationship. Total arsenic concentrations of water and urine were measured by Ionization
Inductively Coupled Plasma-Mass Spectrometry (ICP-MS, Agilent 7500CS, Tokyo, Japan).
2. Materials and methods
2.6. Urinary NAG (renal function) test
2.1. Study site history
Human and rat urinary NAG (N-acetyl-β-glucosaminidase) concentrations were mea-
sured spectrophotometrically using a N-acetyl-β-glucosaminidase commercial assay kit
The first human case of arsenicosis was discovered in Xinjiang Autonomous Re-
(Diazyme, San Diego, USA). The normal range of NAG activity in humans is 0.3–12 IU/L
gion, PR China where over 100,000 people were at risk of arsenic exposure via the
(Price, 1992a; Yuen et al., 1982).
drinking water. The Chepaizi chronic arsenic poisoning areas are located in the west of
Dzungarian Basin in Xinjiang Autonomous Region, China. There are high concentra-
2.7. Blood biomarkers
tions of arsenic in the ground water in an elongated area stretching about 250 km from
Aibi Lake in the southwest of Dzungarian Basin to the east of Marnas River in
The Blood triglyceride (TG), cholesterol (TC), high density lipid (HDL) and low
Dzungarian Basin. Arsenic concentrations in the deep ground water frequently exceed
density lipid (LDL) of all human subjects with or without diabetes in Chepaizi were
0.05 mg/L, and ground water in the newly settled (since 1960s) areas can reach up to
analysed by local pathology laboratory in the hospital.
0.85 mg/L. Between the end of 1970s and early 1980s, this area was confirmed to be
contaminated with arsenic. In 1985, a water improvement project was completed in
3. Results
the area and the residents were thought to be free of arsenic-contaminated drinking
water (Wang et al., 1997).
3.1. Arsenic concentrations in the drinking water

2.2. Sampling — human study
In May 2005, 235 urine and 233 blood samples were collected from villagers with
and without diabetes from the arsenicosis endemic and control areas in Chepaizi,
Xinjiang, PR China. Among the 235 urine samples, 111 were from the arsenicosis en-
demic area (57 diabetes and 54 non-diabetes subjects) in Chepaizi and 124 from a
neighboring control area (72 diabetes and 52 non-diabetes control). Considering the
intervention project was completed 20 years ago, all subjects were in the age of older
than 30 years suggesting that all subjects from the endemic area had at least been living
there for ten years before the water improvement project was carried out.
The arsenic concentrations of the tap water were below 50 µg/L (16–48 µg/L). Well
water arsenic concentrations ranged 36–272 µg/L (Table 1). It was noted that well water
contaminated with elevated arsenic which is not supposed for drinking may still be
drunk during water shortage season in the endemic area.
3.2. Urinary arsenic concentrations
Urinary arsenic concentrations in subjects with or without diabetes from both ar-
senicosis endemic and control areas are shown in Table 2. Urinary arsenic concentrations in
different arsenic exposed groups of rats at different times are shown in Table 3.

Table 2
Urinary arsenic (µg/g crea.), NAG (IU/L) concentrations and blood parameters for the diabetes patients and non-diabetes subjects from both endemic and control areas (mean ± SD)

Sex n As (µg/g crea.) Urinary NAG NAG (IU/L) n Blood glucose n Blood TG Blood TC Blood HDL n Blood LDL
(IU/L) geometric (mM) (mM) (mM) (mM) (mM)
Control area M 30 210.6 ± 3 17.4 ± 14.6 12.54 26 10.3 ± 4.3 30 1.8 ± 1.7 4.4 ± 0.9 1.3 ± 0.2 23 2.9 ± 0.9
diabetes F 42 179.4 ± 10.8 15.1 ± 12.5 11.14 37 9.2 ± 2.6 41 1.7 ± 1.2 5.0 ± 1.5 1.3 ± 0.2 32 3.0 ± 0.9
T 72 192.4 ± 243.4 16.0 ± 13.3 11.7 63 9.7 ± 3.4 71 1.8 ± 1.4 4.8 ± 1.3 1.3 ± 0.2 55 3.0 ± 0.9
Control area M 30 200.8 ± 194.5 11.4 ± 6.3 9.36 28 5.5 ± 0.9 27 1.6 ± 1.0 4.8 ± 1.1 1.4 ± 0.3 25 2.8 ± 0.7
non-diabetes F 22 272.6 ± 237.5 11.5 ± 9.7 7.67 22 6.0 ± 1.0 22 1.8 ± 1.7 4.7 ± 0.9 1.6 ± 0.6 22 2.5 ± 0.7
T 52 231.2 ± 214.5 11.5 ± 7.8 8.6 50 5.8 ± 1.0 49 1.7 ± 1.3 4.7 ± 1.0 1.5 ± 0.5 47 2.7 ± 0.7
Endemic M 21 274 ± 338.8 16.8 ± 12.1 14.5 21 8.2 ± 2.2 21 2.0 ± 0.8 5.3 ± 1.3 1.3 ± 0.2 8 3.0 ± 0.4
area diabetes F 35 359 ± 630.4 16.6 ± 11.8 13.64 30 8.1 ± 2.2 34 1.9 ± 0.7 6.2 ± 2.0 1.3 ± 0.2 12 3.0 ± 0.8
T 56 328.3 ± 533 16.5 ± 11.7 13.85 51 8.1 ± 2.2 55 1.9 ± 0.8 5.9 ± 1.8 1.3 ± 0.2 20 3.0 ± 0.6
Endemic area M 23 183.3 ± 89.9 12.0 ± 7.9 10.69 23 5.6 ± 1.8 22 1.5 ± 0.9 5.3 ± 1.6 1.3 ± 0.2 11 2.8 ± 0.4
non-diabetes F 32 233.2 ± 151.5 12.6 ± 7.4 10.6 30 5.8 ± 1.3 32 2.1 ± 1.6 5.7 ± 1.6 1.4 ± 0.5 15 3.1 ± 0.6
T 55 209 ± 129.5 12.4 ± 7.7 10.67 53 5.7 ± 1.5 54 1.8 ± 1.4 5.5 ± 1.6 1.3 ± 0.4 26 3.0 ± 0.5
All control 124 208.6 ± 231.6 14.12 ± 11.5 10.29 113 8.2 ± 3.9 120 1.7 ± 1.4 4.8 ± 1.2 1.4 ± 0.4 102 2.8 ± 0.8
All endemic 111 270.3 ± 395.3 14.51 ± 10.1 12.18 104 6.9 ± 2.2 109 1.9 ± 1.1 5.7 ± 1.7 1.3 ± 0.3 46 3.0 ± 0.6

M = male, F = female, T = total.

 J.P. Wang et al. / Environment International 35 (2009) 507–511 509

Table 3
Rat urinary NAG (IU/L) and arsenic concentrations (µg/L) before and after exposure to different concentrations of sodium arsenic in drinking water

Rat n Before As exposure 30 days after As exposure 58 days after As exposure 99 days after As exposure 125 days after As exposure
groups mean ± SD mean ± SD mean ± SD mean ± SD mean ± SD
NAG 0 mg/L 6 10.8 ± 2.8 13.7 ± 3.3 14.5 ± 2.4 15.6 ± 3.2 15.4 ± 3.7
(IU/L) 5 mg/L 6 10.6 ± 2.1 11.4 ± 4.6 16.0 ± 3.9 16.2 ± 3.8 16.0 ± 6.7
15 mg/L 6 9.0 ± 3.1 20.2 ± 4.0 20.7 ± 10.5 21.2 ± 4.9 21.9 ± 6.7
30 mg/L 6 6.9 ± 1.9 36.4 ± 9.0 20.1 ± 5.4 22.3 ± 4.7 25.0 ± 8.0
a
As (µg/L) 0 mg/L 6 149.3 ± 56.3 119.7 ± 43.3a 102.3 ± 15.7a 87.0 ± 21.3a 64.0 ± 9.1a
5 mg/L 6 165.8 ± 60.8 2832.4 ± 588.6 7753.1 ± 998.5 7075.6 ± 1626.7 7159.8 ± 1478.3
15 mg/L 6 133.3 ± 46.5 20,721.3 ± 5287.4 43,483.8 ± 12011.7 27,571.3 ± 4599.7 18,182 ± 4364
30 mg/L 6 162.4 ± 71.2 51,255 ± 15959.1 38,338.8 ± 11979.4 58,770 ± 11171.5 31,378 ± 6351.7
a
The average volume of urine for each rat were 10.99 mL, 16.7 mL, 19.48 mL, 18.20 mL and 19.88 mL, respectively, in these five sampling times. SD = standard deviation.

Urinary arsenic concentrations were higher in subjects from the endemic area been carried out for 20 years were significantly higher than those from
compared to those of the controls (P b 0.05). Rats dosed with different arsenic concen-
the nearby control area. In the absence of other known sources, this
trations in their drinking water had corresponding urinary arsenic levels. Urinary arsenic
levels in the control rats decreased with age was due to increased volume of urine indicates, despite the implementation of water intervention project
excretion in older rats. over the past two decades, villagers in Chepaizi arsenicosis ende-
mic areas may still drink arsenic-contaminated water sporadically
3.3. Blood parameters especially during water shortage season. The subjects employed in
this study were all over 30 years of age and most of them in the age of
Blood parameters for patients with and without diabetes from both endemic and 50–60 years representing about 73% in endemic and 65% in control
control areas are shown in Table 2. There were no significant differences among in- areas studied groups. Since they have been living in this area for more
dividuals for HDL and LDL.
than 30 years which suggests they have been exposed to high arsenic
Villagers with or without diabetic conditions from arsenic-endemic area had higher
TC concentrations than their respective counterparts from the control area (P b 0.01). in the natural environment for at least 10 years noting that the water
Female patients had higher TC levels than males (P b 0.05). improvement project in this area was completed in 1985. In a previous
As expected, diabetic subjects had higher blood glucose compared to non-diabetes
subjects. However, the blood glucose levels in diabetic patients from the endemic areas
were significantly lower than those of control patients (P b 0.05) and same results were
found in the overall population (P b 0.05).
Rats blood glucose and BGTT (Blood glucose tolerance test) results from different
groups of rats at different time intervals after exposure to arsenic are shown in Table 4
and Figs. 1 and 2.
Alteration of glucose tolerance test results were found in the arsenic exposed
groups (glucose levels were significantly lower than the controls at time 15, 30, and
60 min) after exposure to arsenic for 182 days (Fig. 1 [A]), but no differences were
observed after exposure to arsenic for 242 days (Fig. 1 [B]).
Rat blood glucose levels clearly were not influenced by exposure to arsenic for
242 days (Table 4), but arsenic seemed to have restrained the degree of STZ-induced-
diabetes condition (causing blood glucose reduction, Fig. 2).

3.4. Renal function biomarker (urinary NAG concentrations)

Urinary NAG concentrations in villagers with or without diabetes from endemic area
were higher than the corresponding groups from the control area. In addition, urinary NAG
concentrations were significantly higher in villagers with diabetes than those without the
symptoms, and the mean value of urinary NAG in all groups of subjects from the endemic
area exceeded the normal range of 0.3–12 IU/L compared to most of subjects in the control
groups whose NAG levels were within this range (Table 2 and Fig. 3).
Elevation of urinary NAG concentrations in rats exposed to different arsenic con-
centrations in their drinking water and at different exposure times was also observed
when compared to the control group of rats (Table 3). Volumes of water consumed and
urine excreted by rats from different arsenic exposure groups were adjusted with an
index ratio calculated by using the urine volumes from different groups.
Elevated NAG in the urine and lower blood glucose in diabetic patients were con-
sistent to those observed in the rat model.

4. Discussion and conclusion

Results in this study indicated the urinary arsenic concentrations

in residents from arsenicosis endemic areas where intervention had

Table 4
Rat blood glucose levels (mM) in different arsenic treated groups at different intervals
post treatment time

Rat n Before As n 140 days na 155 days na 170 days na 210 days
group exposure
0 mg/L AsIII 8 5.0 ± 0.3 8 6.0 ± 0.4 6 5.8 ± 0.3 6 5.9 ± 0.9 6 5.5 ± 0.8
5 mg/L AsIII 8 5.0 ± 0.3 8 5.8 ± 0.7 5 5.6 ± 0.3 6 5.3 ± 0.1 6 5.3 ± 0.5
15 mg/L AsIII 8 5.2 ± 0.3 8 6.2 ± 0.4 5 5.6 ± 0.4 6 5.5 ± 0.4 6 5.2 ± 0.4
30 mg/L AsIII 8 5.3 ± 0.4 8 6.1 ± 0.2 5 5.8 ± 0.5 6 6.0 ± 0.5 6 5.6 ± 1.0
a
Rats numbers differ owing to some rats were not able to obtain the tail blood at the Fig. 1. Blood glucose tolerance test on rats after exposure to different levels of arsenic in
testing time or grouped to STZ injection groups (6 each group) in later time. drinking water for 182 days [A] and for 242 days [B].
510 J.P. Wang et al. / Environment International 35 (2009) 507–511
Fig. 2. Rat blood glucose levels (mM) on different days after induction of diabetes by a
single intravenous injection of STZ (35 mg/kg bw) in different arsenic exposed groups
(n = 6).
study on all population there (the study carried out in 2002 and detail
will be published soon), we noticed that urinary arsenic level had
an accumulation trend with the increase of age and 25.3% (44/174)
people from the arsenic-endemic area of Chepaizi were found to
display symptoms of arsenicosis, most of the arsenicosis individual
cases (93.2%) were in people over 30 years old (among them 77.3%
(34/44) were over 50 years old). This paper addressed specifically on
the population in this age range.
Our results suggested that arsenic affect the kidney function sig-
nificantly in individuals with diabetic conditions. Kidney is susceptible
to secondary damage resulting from diseases such as hypertension
and diabetes. Several studies in endemic areas of Taiwan and Bang-
ladesh have provided evidence of an association of arsenic exposure
with diabetes mellitus (Lai et al., 1994; Tseng et al., 2000, 2002, 2004;
Rahman and Axelson, 1995; Rahman et al., 1996, 1998, 1999).
Researchers have noticed the higher prevalence of diabetes in Che-
paizi endemic areas where this study was carried out (personal com-
munication with Xinjiang CDC scientists — S.L. Wang and L.F. Wang).
The high reserve capacity of the kidney means that over 50% of active
renal mass can be lost before there is a measurable change in renal
function, this explains the kidney is relatively less sensitive to chronic
arsenic exposure than most other organ system (ASTDR, 2000). Our
results show that urinary NAG concentrations in endemic diabetes
and control diabetes subjects were 16.5 IU/L and 16.0 IU/L as the
arithmetic mean and 13.85 IU/L and 11.7 IU/L as the geometric mean,
respectively. These were significantly higher than those without dia-
betes. The renal function alteration in diabetes subjects of this study
indicated the effect of both arsenic exposure and diabetes on this
organ.
The significant finding in this study is the elevation of urinary NAG
level after exposure to arsenic both in humans and rats. Elevated urinary
NAG levels are indicative of kidney dysfunction. NAG is a lysosomal en-
zyme involved in the breakdown metabolism of glycoproteins. Increased
NAG levels in the urine are an early indication of renal disease and can
serve as a valuable renal function test in disorders such as nephritis
syndrome and other diseases associated nephropathy (Price, 1992b).
Previous reports have shown the interaction between arsenic and cad-
mium to produce nephrotoxicity both in mice (Liu et al., 2000) and
humans (Buchet et al., 2003; Nordberg et al., 2005; Hong et al., 2004).
Evidence of renal toxicity upon exposure to arsenic is limited to animal
models using relatively high dose (WHO, 1992, 2001) although chronic
arsenic exposure have been associated with kidney cancer. In our human
study, overall urinary NAG concentrations in all population from the
endemic areas and the percentage of urinary NAG level that was over
12 IU/L (the upper range in health subjects) were both higher than those
from the control area (geometric mean 12.18 IU/L compared to 10.29 IU/L,
49.5% and 46.0% in percentage, respectively), and another significant
observation is the higher urinary NAG in non-diabetes people exposed to
arsenic than those from the control area (12.4 IU/L and 11.5 IU/L in the
mean, 10.67 IU/L and 8.5 IU/L in geometric mean, respectively). Both
animal and humans were studied and the corresponding results of
elevated urinary NAG levels after arsenic exposure support the renal
toxicity of arsenic exposure alone. This appears to be the most significant
biomarker among all parameters measured here.
The causal relationship of arsenic exposure and diabetes mellitus
has not reached the consensus so far. Epidemiological studies in ar-
senicosis endemic areas mostly supported the association of chronic
arsenic exposure and diabetes mellitus, but the biological mechanisms
for the association are not known (Navas-Acien et al., 2006). Impaired
glucose tolerance is an early indicator of insulin resistance and dia-
betes mellitus. Previous reports on the effects of arsenic exposure on
glucose homeostasis and in-vivo insulin and carbohydrate metabolism
in laboratory animals have been inconsistent owing to the variations
in selected animal species and arsenicals, as well as route, concentra-
tion and duration of exposure (Navas-Acien et al., 2006; Paul et al.,
2007a). Our study both in humans and rats has afforded several con-
sistent observations: arsenic alters glucose metabolism significantly in
individuals with diabetes; and chronic arsenic exposure has the
inhibitory effect on glucose metabolism both in humans and rats. The
blood glucose tolerance test (BGTT) in rats demonstrated time and
dose-related alteration with the arsenic exposure. Inhibitory effect of
arsenic on blood glucose level was observed in BGTT after 182 days in
all arsenic exposed groups, but this inhibitory effect were no longer
observed in BGTT after 242 days, in which rats from the 5 mg/L arsenic
exposed group showed impaired glucose tolerance but with increasing
blood glucose levels at 15, 30 and 60 min when compared with other
groups of rats. The significance of this observation in arsenic dia-
betogenic effect needs further investigations.
Fig. 3. Urinary NAG concentrations (IU/L, geometric mean) by gender and diabetes
conditions from both arsenicosis control and endemic areas (cdm = control area male
diabetes, cdf = control area female diabetes, cdt = total diabetes from control area, cndm =
control area male non-diabetes, cndf = control area female non-diabetes, cndt = total
non-diabetes from control area, edm = endemic area male diabetes, edf = endemic area
female diabetes, edt = total diabetes from endemic area, endm = endemic area male non-
diabetes, endf = endemic area female non-diabetes, cndt = endemic area all non-diabetes,
all control = all subjects with or without diabetes from control area, all endemic = all
subjects with or without diabetes from endemic area.).
 J.P. Wang et al. / Environment International 35 (2009) 507–511
Insulin resistance and β-cell dysfunction can be induced by chronic
arsenic exposure, which could be putatively explained by current
knowledge of the biochemical properties of arsenic. Arsenate can sub-
stitute phosphate in the formation of adenosine triphosphate (ATP) and
other phosphate intermediates involved in glucose metabolism.
Arsenite has high affinity for sulfhydryl groups and thus can form
covalent bands with the disulfide bridges in the molecules of insulin,
insulin receptors, glucose transporters (GLUTs), and enzymes involved
in glucose metabolism. But these effects have no evidence of occurrence
in the chronic arsenic exposure conditions (Tseng, 2004). Arsenic and its
methylated metabolites can induce oxidative stress and interferences in
the signal transduction or gene expression of insulin synthesis. This
could be the most possible causes to arsenic-induced diabetes mellitus
through mechanisms of induction of insulin resistance and β-cell
dysfunction (Yamanaka et al., 1990; Kitchin et al., 2003; Shi et al., 2004;
Liu et al., 2001; Pi et al., 2002; Wu et al., 2001). Our previous study
carried out in the Chepaizi arsenicosis endemic area found a correlation
of urinary MDA (malondialdehyde, an oxidative stress biomarker) and
urinary arsenic concentrations in local residents. Urinary MDA con-
centrations significantly elevated in people with high urinary arsenic
compared to those from the control area (The 2002 survey data will be
published soon). Many other risk factors of diabetes mellitus can in-
fluence the toxicity of arsenic on organs involved in glucose metabolism.
Whether oxidative stress induced by arsenic plays role in diabetes
remains unclear. Arsenic toxicity can also interfere with the progression
of insulin resistance and impaired insulin secretion to a status of per-
sistent hyperglycemia or diabetes mellitus (Tseng, 2004; Izquierdo-Vega
et al., 2006; Walton et al., 2004; Paul et al., 2007b). The causal
relationship of chronic arsenic exposure and diabetes mellitus and the
biological mechanisms are yet to be determined and will require further
investigations. The rodent model is useful for this type of studies.
Acknowledgements
EnTox is a partnership between Queensland Health and the Uni-
versity of Queensland. JPW is partially funded by CRC-CARE.
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